Rilmenidine is a Calorie Restriction Mimetic that Improves Survival and Indicators of Healthy Ageing in C. elegans via a Novel IRAS Ortholog, f13e9.1

Ageing is currently the inevitable consequence of human existence. The ageing process is a disease that internally imposes limitations and reductions in liberty through enfeeblement, frailty and pathology, leading to dramatic physiological and psychological suffering. Therefore, it is paramount we identify immediate strategies which defer the progression of age-associated diseases and compress morbidity. At present, calorie restriction (CR) offers the most feasible and robust intervention to decelerate ageing. However, despite the attractive pro-longevity effects of CR, several concerns surrounding the applicability, tolerability and safety have precluded its widespread adoption. Using the Connectivity Map to identify drugs with a similar transcriptome to CR, I sought to repurpose a clinically approved drug that demonstrated broad tolerability and safety whilst representing an easily translatable, potential calorie restriction mimetic. I identified rilmenidine: a widely-prescribed, centrally-acting antihypertensive that mimicked gene expression changes previously observed in CR. Furthermore, rilmenidine significantly opposed the transcriptional direction of ageing such that it rescued age-associated overexpression of genes enriched for immune-regulation, inflammation and ECM degradation. I validated the potential geroprotective properties of rilmenidine in the model organism C. elegans. Rilmenidine administration extended lifespan in WT worms, when commenced from early adulthood or only once the worm had aged. Furthermore, it decelerated the development of decrepitude, without altering developmental periods. Lifespan extension was not possible in genetic models of CR (eat-2), suggesting a longevity effect was induced through CR mimicry. Moreover, this was supported by rilmenidine-induced lifespan effects being dependent on 3 key CR nexuses: DAF-16, AMPK and TOR. In C. elegans, Rilmenidine elicited increases in ERK activity, typical of in-vitro imidazoline agonist exposure, which was abrogated following blockade of an imidazoline binding site. This effect was mimicked following the knockout of f13e9.1, which was characterised herein as the nematode ortholog of the human imidazoline type 1 receptor (IRAS). Indeed, rilmenidine also increased nematode thermotolerance as well as autophagy, both dependent on imidazoline binding, and demonstrated a capacity to attenuate the accumulation of polyQ aggregates. Autophagy was essential to the longevity effect of rilmenidine and was increased independent of the previously hypothesised cAMP pathway. Thus, this research presents a strong novel case for rilmenidine to be a CR mimetic that warrants substantial clinical investigation as to the auxiliary benefits of rilmenidine which may belie its overt purpose as an anti-hypertensive, such that it be preferentially prescribed to hypertensives which provides a safe, tolerable method of CR mimicry to over 25% of the population

The role of visual adaptation in cichlid fish speciation

D. Shane Wright (1) , Ole Seehausen (2), Ton G.G. Groothuis (1), Martine E. Maan (1) (1) University of Groningen; GELIFES; EGDB(2) Department of Fish Ecology & Evolution, EAWAG Centre for Ecology, Evolution and Biogeochemistry, Kastanienbaum AND Institute of Ecology and Evolution, Aquatic Ecology, University of Bern.In less than 15,000 years, Lake Victoria cichlid fishes have radiated into as many as 500 different species. Ecological and sexual sel ection are thought to contribute to this ongoing speciation process, but genetic differentiation remains low. However, recent work in visual pigment genes, opsins, has shown more diversity. Unlike neighboring Lakes Malawi and Tanganyika, Lake Victoria is highly turbid, resulting in a long wavelength shift in the light spectrum with increasing depth, providing an environmental gradient for exploring divergent coevolution in sensory systems and colour signals via sensory drive. Pundamilia pundamila and Pundamilia nyererei are two sympatric species found at rocky islands across southern portions of Lake Victoria, differing in male colouration and the depth they reside. Previous work has shown species differentiation in colour discrimination, corresponding to divergent female preferences for conspecific male colouration. A mechanistic link between colour vision and preference would provide a rapid route to reproductive isolation between divergently adapting populations. This link is tested by experimental manip ulation of colour vision - raising both species and their hybrids under light conditions mimicking shallow and deep habitats. We quantify the expression of retinal opsins and test behaviours important for speciation: mate choice, habitat preference, and fo raging performance